Small molecule inhibitors of ubiquitin specific protease 1 (USP1) and uses thereof
The disclosure provides for small molecules inhibitory compounds of ubiquitin specific protease 1 (USP1) and compositions comprising the same. The disclosure further provides methods for targeting ubiquitin specific protease 1 (USP1) and methods of treating diseases or disorders related to USP1, such as cancer.
1. A compound having the structure of Formula (IVa-2), or a pharmaceutically acceptable salt thereof,
wherein
Y 1 is N or CR Y1 ;
Y 2 is N or CR Y2 ;
Y 3 is CR Y3 ;
Y 4 is CR Y4 ;
each of R Y1 , R Y2 , R Y3 , and R Y4 is independently hydrogen or C 1 -C 6 alkyl;
R 1 is hydrogen or C 1 -C 6 alkyl;
and each R A is independently OH, C 1-6 alkoxyl, C 1-6 alkyl, C 1-6 haloalkyl, or C 3 -C 6 cycloalkyl; and
R B1 is 5 membered heteroaryl optionally substituted with one or more substituents selected from C 1-3 haloalkyl and C 1-3 alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Y 1 is CH, Y 2 is CH, Y 3 is CH, and Y 4 is CH;
Y 1 is CH, Y 2 is N, Y 3 is CH, and Y 4 is CH; or
Y 1 is N, Y 2 is CH, Y 3 is CH, and Y 4 is CH.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R B1 is
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
15. A method of treating a disease or disorder associated with ubiquitin specific protease 1 (USP1) comprising administering to a subject a compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the subject has a disease or disorder associated with USP1.
16. The method of claim 15 , wherein the disease or disorder is a cancer, and wherein the cancer is a BRCA1 mutant cancer, a BRCA2 mutant cancer, or a BRCA1 and BRCA2 mutant cancer.
17. The method of claim 15 , wherein the disease or disorder is a cancer, and wherein the cancer is a DNA damage repair pathway deficient cancer.
18. The method of claim 15 , wherein the disease or disorder is a cancer, and wherein the cancer is a homologous recombination deficient (HRD) cancer.
19. A pharmaceutical composition comprising (i) a compound having the structure of Formula (IVa-2), or a pharmaceutically acceptable salt thereof,
wherein
Y 1 is N or CR Y1 ;
Y 2 is N or CR Y2 ;
Y 3 is CR Y3 ;
Y 4 is CR Y4 ;
each of R Y1 , R Y2 , R Y3 , and R Y4 is independently hydrogen or C 1 -C 6 alkyl;
R 1 is hydrogen or C 1 -C 6 alkyl;
and each R A is independently OH, C 1-6 alkoxyl, C 1-6 alkyl, C 1-6 haloalkyl, or C 3 -C 6 cycloalkyl; and
R B1 is 5 membered heteroaryl optionally substituted with one or more substituents selected from C 1-3 haloalkyl and C 1-3 alkyl; and
(ii) a pharmaceutically acceptable excipient.
20. The pharmaceutical composition of claim 19 , wherein:
Y 1 is CH, Y 2 is CH, Y 3 is CH, and Y 4 is CH;
Y 1 is CH, Y 2 is N, Y 3 is CH, and Y 4 is CH; or
Y 1 is N, Y 2 is CH, Y 3 is CH, and Y 4 is CH.
21. The pharmaceutical composition of claim 19 , wherein R 1 is —CH 3 ;
and R B1 is
22. The pharmaceutical composition of claim 19 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
23. The pharmaceutical composition of claim 19 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
24. The pharmaceutical composition of claim 19 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
25. The pharmaceutical composition of claim 19 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
26. The pharmaceutical composition of claim 19 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
27. The pharmaceutical composition of claim 19 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
28. The pharmaceutical composition of claim 19 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
29. The pharmaceutical composition of claim 19 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
30. The pharmaceutical composition of claim 19 , wherein the compound is
or a pharmaceutically acceptable salt thereof.